Immunotherapy with live bacterium improves response rate in malignant pleural mesothelioma
GENEVA, Switzerland, 14 April 2016 – [ESMO PRESS RELEASE] Immunotherapy with a live bacterium combined with chemotherapy demonstrated more than 90% disease control and 59% response rate in patients with malignant pleural mesothelioma (MPM), according to the results of a phase Ib trial presented today at the European Lung Cancer Conference (ELCC) 2016 in Geneva, Switzerland.1
“Malignant pleural mesothelioma is a cancer of the lining of the lung and is rare but difficult to treat,” said Prof Thierry Jahan, professor of medicine at the UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco, US. “Standard of care treatment with pemetrexed and platinum compound chemotherapy gets a 30% response rate but a modest impact on survival. So there is a clear unmet need in targeting this specific population.”
Patients with MPM strongly express the mesothelin antigen in the tumour. CRS-207 is a live, attenuated Listeria monocytogenes bacterium that contains two gene deletions to diminish its pathogenicity and has also been engineered to express mesothelin.
“In our early studies, CRS-207 induced an anti-mesothelin response and cellular tumour specific immunity in patients with mesothelin expressing tumours,” said Jahan. “We also have data suggesting that this immunotherapy works synergistically with chemotherapy, so testing the effect of this immune targeting agent with chemotherapy was a natural step.”
The current study examined the impact of CRS-207 combined with standard chemotherapy in patients with advanced unresectable mesothelioma who were candidates for chemotherapy. It included 38 patients who received two CRS-207 infusions two weeks apart, up to six cycles of pemetrexed plus cisplatin three weeks apart, followed by two additional CRS-207 infusions three weeks apart. Eligible patients received maintenance CRS-207 every eight weeks. Patients were followed every eight weeks until disease progression.
After a median follow up of 9.4 months (range: 0.2–28.1 months), the investigators found that 59% of patients had partial response and 35% had stable disease, for an overall 94% disease control rate. Median progression free survival was 8.5 months. Jahan said: “Patients receiving the combination of CRS-207 and chemotherapy had a deep response, with more than 90% disease control.”
The primary side-effects associated with CRS-207 administration were temperature spike and rigors. These were related to the infusion and resolved within 24 hours. “The safety of the agent was remarkable,” said Jahan. “It really does appear to be safe, and was well-tolerated in combination with pemetrexed and platinum chemotherapy. There didn’t seem to be any cumulative toxicity.”
Immunohistochemistry analysis in three patients showed marked recruitment and expansion of tumour infiltrating leukocytes following the administration of the therapy. There was also an enhancement of infiltrating CD8+ cells, macrophages and natural killer cells.
Jahan said: “We saw good immune activation which confirmed the preclinical hypotheses for utilising this agent. It appears to activate both innate and adaptive immunity and then develops a synergistic efficacy with the chemotherapy.”
He concluded: “CRS-207 is an exciting agent for patients with mesothelioma. Our preliminary results are encouraging, suggesting superior clinical activity when added to standard chemotherapy. This supports assessing the impact of CRS-207 in a randomised trial, which is currently in the planning stages and should be underway within this calendar year.”
Commenting on the research, Prof Rolf Stahel, Professor of oncology at the University Hospital Zurich in Zurich, Switzerland, said: “The findings suggest that the addition of this type of immunotherapy improves the response rate, and provides a longer progression free survival, compared to what would be expected with chemotherapy alone. This supports the hypothesis of benefit of this vaccination which will be examined in a randomised trial to prove or disprove the survival benefit of vaccination added to chemotherapy.”
1) 208O_PR: CRS-207 with chemotherapy (chemo) in malignant pleural mesothelioma (MPM): Results from a phase 1b trial. T. Jahan, US. Thursday 14th April 2016 – 17:45-18:00 Multidisciplinary management of thoracic malignancies Room A
CRS-207 with chemotherapy (chemo) in malignant pleural mesothelioma (MPM): Results from a phase 1b trial
T. Jahan1, R. Hassan2, E. Alley3, H. Kindler4, S. Antonia5, C. Whiting6, L. Coussens7, A.L. Murphy6, A. Thomas2, D.G. Brockstedt6
1Department of Medicine, Division of Hematology Oncology, University of California San Francisco UCSF, San Francisco, CA, USA, 2Thoracic and GI Oncology Branch, National Cancer Institute, Bethesda, MD, USA, 3Division of Hematology/Oncology, University of Pennsylvania, Philadelphia, PA, USA, 4Gastrointestinal Oncology and Mesothelioma Programs, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA, 5Department of Thoracic Oncology, H Lee Moffitt Cancer Center, Tampa, FL, USA, 6Clinical and Research Development, Aduro Biotech, Inc., Berkeley, CA, USA, 7Cell, Developmental & Cancer Biology Department, Oregon Health & Science University, Portland, OR, USA
Background: MPM is an aggressive disease with poor prognosis. CRS-207 is live, attenuated, double-deleted Listeria monocytogenes engineered to express the tumor-associated antigen mesothelin, activating innate and adaptive immunity. The combination of CRS-207 and chemo may act synergistically to alter the tumor microenvironment to potentiate immune-mediated killing.
Methods: Eligible patients (pts) were chemo-naïve with unresectable MPM, ECOG 0-1, and adequate organ function. Patients received 2 CRS-207 infusions (1×109 CFU) 2 weeks apart, 6 cycles of pemetrexed (500 mg/m2) plus cisplatin (75 mg/m2) 3 weeks apart, followed by 2 additional CRS-207 infusions 3 weeks apart. Eligible patients received maintenance CRS-207 every 8 weeks; all patients were followed every 8 weeks until disease progression.. Study objectives include safety, immunogenicity, tumor response and tumor marker kinetics. Immune analyses included multiplexed immunohistochemistry (IHC) of tumor-infiltrating lymphocytes (TILs), flow cytometry analysis of peripheral blood mononuclear cells, and Luminex analysis of serum biomarkers.
Results: As of August 2015, 38 pts have been enrolled. The most commonly reported CRS-207-related adverse events include grades 1/2 infusion-related fever, chills/rigors, hypotension and nausea/vomiting with no treatment-related serious adverse events or deaths. Of evaluable pts, 59% (20/34) had partial response post-treatment and 35% (12/34) had stable disease for overall 94% disease control rate. Median progression-free survival (PFS) was 8.5 months (mos); median overall survival had not been reached. IHC data from 3 patients revealed an increase in TILs post-CRS-207. Treatment-associated changes in circulating immune cells and biomarkers were also observed.
Conclusions: CRS-207 has been well tolerated and in combination with chemo showed encouraging anti-tumor activity with 59% response rate and median PFS of 8.5 mos. Recruitment and expansion of TILs and changes in circulating immune cells and serum biomarkers were observed post-CRS-207. These results appear considerably better than those expected with chemo alone and will be evaluated in a Phase 3 trial.
Clinical trial identification: NCT01675765
Legal entity responsible for the study: Aduro Biotech, Inc.
Funding: Aduro Biotech, Inc.
T. Jahan: Member of Aduro Mesothelioma Steering Committee. R. Hassan, E. Alley, H. Kindler: Member of Aduro Steering Committee. C. Whiting, A.L. Murphy, D.G. Brockstedt: Aduro stock owner. All other authors have declared no conflicts of interest.
Keywords: malignant pleural mesothelioma, live attenuated double-deleted listeria (LADD), first line, immunotherapy of cancer